Intranasal and transdermal administration of kappa-opioid-receptor agonists: salvinorin a for the treatment of neuropsychiatric and addictive disorders

ABSTRACT

Methods of treating neuropsychiatric disorders including affective disorders and addiction involve intranasal or transdermal administration of a substantially selective kappa-opioid-receptor agonist that is also a partial D2 agonist, such as the compound salvinorin A. Also disclosed are intranasal, transdermal and/or inhalation systems for delivering the kappa-opioid-receptor agonist.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation application of application Ser. No. 15/354,078, filed Nov. 17, 2016, which claims the benefit of U.S. Provisional Application No. 62/256,409, filed Nov. 17, 2015, both of which are incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION (1) Field of the Invention

The present invention is related to the treatment of neuropsychiatric conditions with kappa-opioid-receptor agonists and, in particular, to intranasal, transdermal and inhalation systems and methods of administration of kappa-opioid-receptor agonists for the treatment of neuropsychiatric conditions.

(2) Description of the Related Art

Salvinorin A is a naturally occurring psychoactive compound isolated from Salvia divinorum. Studies have demonstrated that salvinorin A is a uniquely selective kappa-opioid-receptor agonist with no significant effect on a battery of 50 other receptors, transporters and ion channels including mu- and delta-opioid receptors (Roth et al., 2004). In addition to having kappa-opioid-agonist activity, salvinorin A has been found to be a D2 receptor partial agonist (Seeman et al., 2009). Notably, salvinorin A has been shown to have no significant effect on 5HTP_(2A) receptors and as a result, administration of salvinorin A to a subject would not be expected to produce mania (Yatham et al., 2010). Recent studies have suggested that salvinorin A may have anti-depression and anti-addiction properties among other potentially beneficial properties (Morani et al., 2009; Prevatt-Smith et al, 2011; Harden et al., 2012; Orton et al., 2014).

Several routes of administration have been used for Salvia divinorum and for salvinorin A with varying degrees of success. In traditional practice among the Mazatec people of Mexico, Salvia divinorum was ingested by chewing the fresh leaves as a quid or by smoking (Valdes, 1994; Siebert, 1994). Absorption upon chewing is apparently by the buccal route in as much as encapsulated salvinorin A is inactive when administered orally (Siebert, 1994; Ott, 1995). Sublingual administration has generally yielded inconsistent results or no absorption at all (Siebert, 1994; Mendelson et al., 2011). The most common route of administration of Salvia divinorum has been inhalation by smoking the leaves (Giroud et al., 2000). More recently, the inhalation route of administration has been used for the active component, salvinorin A, in human subjects (Johnson et al., 2011; Maqueda et al., 2015).

Although infrequently used, the intranasal route of administration has been proposed for use in pharmacologic treatment of neuropsychiatric conditions. Potential advantages of intranasal administration are rapid onset of action, the ability to bypass the blood-brain barrier, improvement in bioavailability and avoidance of parenteral administration (Andrade, 2015). Nevertheless, there are numerous challenges and potential problems that have limited the use of intranasal administration of drugs for the treatment of neuropsychiatric conditions (Dhuria, 2010; Djupesland, 2014). In spite of this, the neuropsychiatric drug ketamine is currently under experimental investigation using the intranasal route of administration for treatment of acute and chronic pain, autism, depression and other conditions (Afridi, 2013; Yeaman, 2014; Clark, 2014, Lapidus, 2014; Graudins, 2015). Naltrexone can potentiate the effects of ketamine (Krystal et al., 2006).

Similar to the intranasal route of administration, transdermal administration presents challenges and only a few medications can be delivered through the transdermal route in therapeutic amounts (Paudel, 2010; Ita, 2015).

As noted above, numerous studies have evaluated different routes of administration for salvinorin A. Nevertheless, none of the routes of administration that have been studied are particularly suited for use in neuropsychiatry.

BRIEF SUMMARY OF THE INVENTION

Accordingly, the applicant herein has invented an intranasal system and method and a transdermal system and method for administration of kappa-opioid-selective agonists such as salvinorin A, for the treatment of neuropsychiatric conditions.

Thus in various embodiments, the present invention involves a method of treating an affective disorder in a patient in need thereof. The method may comprise administering intranasally to the patient, a therapeutically effective amount of a substantially selective kappa-opioid-receptor agonist in a pharmaceutically acceptable preparation. In various embodiments, the kappa-opioid-receptor agonist may be devoid of activity on 5HT₂ receptors, in particular 5HT_(2A) receptors, such that it produces substantially no manic effect. In various embodiments, the kappa-opioid-receptor agonist also has D2 agonist activity and, in particular, partial D2 agonist activity. In certain embodiments, the kappa-opioid-receptor agonist may be salvinorin A. Administration may be with an intranasal delivery device.

In various embodiments, the affective disorder may be depression, bipolar disorder or anxiety disorder.

In various aspects of this embodiment, the kappa-opioid-receptor agonist may be administered with either or both of a cannabinoid compound and ketamine in a pharmaceutically acceptable preparation. The pharmaceutically acceptable preparation for the cannabinoid compound and/or ketamine may include the same carrier system in which the kappa-opioid-receptor agonist is administered and the substances may be administered together or separately in any combination thereof. Alternatively, the carrier system for the cannabinoid compound and/or ketamine may be different from that of the kappa-opioid-receptor agonist and the substances may be administered separately. In some embodiments, naltrexone is included.

In various embodiments, the present invention may involve a method of treating addiction in a subject in need thereof. The method may comprise administering intranasally to the patient, a therapeutically effective amount of a substantially selective kappa-opioid-receptor agonist in a pharmaceutically acceptable preparation. In various embodiments, the kappa-opioid-receptor agonist may be devoid of activity on 5HT₂ receptors, in particular 5HT_(2A) receptors, such that it produces substantially no manic effect. In various embodiments, the kappa-opioid-receptor agonist also has D2 agonist activity and, in particular, partial D2 agonist activity. In certain embodiments, the kappa-opioid-receptor agonist may be salvinorin A. Administration may be with an intranasal delivery device.

In various embodiments, the addiction may be an addiction to nicotine, cocaine, opioids, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well as other addictive substances and addictive behaviors.

In various aspects of this embodiment, the kappa-opioid-receptor agonist may be administered with either or both of a cannabinoid compound and ketamine in a pharmaceutically acceptable preparation. The pharmaceutically acceptable preparation for the cannabinoid compound and/or ketamine may include the same carrier system in which the kappa-opioid-receptor agonist is administered and the substances may be administered together or separately in any combination thereof. Alternatively, the carrier system for the cannabinoid compound and/or ketamine may be different from that of the kappa-opioid-receptor agonist and the substances may be administered separately. In some embodiments, naltrexone is included.

In yet another embodiment, the present invention may involve an intranasal delivery system. The system may comprise an intranasal delivery device and a therapeutically effective amount of a substantially selective kappa-opioid-receptor agonist in a pharmaceutically acceptable preparation. In various embodiments, the kappa-opioid-receptor agonist may be devoid of activity on 5HT₂ receptors, in particular 5HT_(2A) receptors, such that it does not produce mania. In various embodiments, the kappa-opioid-receptor agonist also has D2 agonist activity and, in particular, partial D2 agonist activity. In certain embodiments, the kappa-opioid-receptor agonist may be salvinorin A.

In various aspects of this embodiment, the system may include, in addition to the kappa-opioid-receptor agonist, either or both of a cannabinoid compound and ketamine in a pharmaceutically acceptable preparation. The pharmaceutically acceptable preparation for the cannabinoid compound and/or ketamine may include the same carrier system in which the kappa-opioid-receptor agonist is administered and the substances may be administered together or separately in any combination thereof. Alternatively, the carrier system for the cannabinoid compound and/or ketamine may be different from that of the kappa-opioid-receptor agonist and the substances may be administered separately. In some embodiments, naltrexone is included.

In various other embodiments, the present invention may involve an inhalation delivery system. The system may comprise an inhalation delivery device and a therapeutically effective amount of a substantially selective kappa-opioid-receptor agonist in a pharmaceutically acceptable preparation. In various embodiments, the kappa-opioid-receptor agonist may be devoid of activity on 5HT₂ receptors, in particular 5HT_(2A) receptors, such that it produces substantially no manic effect. In various embodiments, the kappa-opioid-receptor agonist also has D2 agonist activity and, in particular, partial D2 agonist activity. In certain embodiments, the kappa-opioid-receptor agonist may be salvinorin A.

In various aspects of this embodiment, the system may include, in addition to the kappa-opioid-receptor agonist, either or both of a cannabinoid and ketamine in a pharmaceutically acceptable preparation. The pharmaceutically acceptable preparation for the cannabinoid compound and/or ketamine may include the same carrier system in which the kappa-opioid-receptor agonist is administered and the substances may be administered together or separately in any combination thereof. Alternatively, the carrier system for the cannabinoid compound and/or ketamine may be different from that of the kappa-opioid-receptor agonist and the substances may be administered separately. In some embodiments, naltrexone is included.

In various other embodiments, the present invention involves a method of treating an affective disorder in a patient in need thereof. The method may comprise administering transdermally to the patient, a therapeutically effective amount of a substantially selective kappa-opioid-receptor agonist in a pharmaceutically acceptable preparation. In various embodiments, the kappa-opioid-receptor agonist may be devoid of activity on 5HT₂ receptors, in particular 5HT_(2A) receptors, such that it produces substantially no manic effect. In various embodiments, the kappa-opioid-receptor agonist also has D2 agonist activity and, in particular, partial D2 agonist activity. In certain embodiments, the kappa-opioid-receptor agonist may be salvinorin A. Administration may be with a transdermal delivery device or system.

In various embodiments, the affective disorder may be depression, bipolar disorder or anxiety disorder.

In various aspects of this embodiment, the kappa-opioid-receptor agonist may be administered with either or both of a cannabinoid compound and ketamine in a pharmaceutically acceptable preparation. The pharmaceutically acceptable preparation for the cannabinoid compound and/or ketamine may include the same carrier system in which the kappa-opioid-receptor agonist is administered and the substances may be administered together or separately in any combination thereof. Alternatively, the carrier system for the cannabinoid compound and/or ketamine may be different from that of the kappa-opioid-receptor agonist and the substances may be administered separately. In some embodiments, naltrexone is included.

In various embodiments, the present invention may involve a method of treating addiction in a subject in need thereof. The method may comprise administering transdermally to the patient, a therapeutically effective amount of a substantially selective kappa-opioid-receptor agonist in a pharmaceutically acceptable preparation. In various embodiments, the kappa-opioid-receptor agonist may be devoid of activity on 5HT₂ receptors, in particular 5HT_(2A) receptors, such that it produces substantially no manic effect. In various embodiments, the kappa-opioid-receptor agonist also has D2 agonist activity and, in particular, partial D2 agonist activity. In certain embodiments, the kappa-opioid-receptor agonist may be salvinorin A. Administration may be with a transdermal delivery device or system.

In various embodiments, the addiction may be an addiction to nicotine, cocaine, opioids, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well as other addictive substances and addictive behaviors.

In various aspects of this embodiment, the kappa-opioid-receptor agonist may be administered with either or both of a cannabinoid compound and ketamine in a pharmaceutically acceptable preparation. The pharmaceutically acceptable preparation for the cannabinoid compound and/or ketamine may include the same carrier system in which the kappa-opioid-receptor agonist is administered and the substances may be administered together or separately in any combination thereof. Alternatively, the carrier system for the cannabinoid compound and/or ketamine may be different from that of the kappa-opioid-receptor agonist and the substances may be administered separately. In some embodiments, naltrexone is included.

In yet another embodiment, the present invention may involve a transdermal delivery system. The system may comprise a transdermal delivery device and a therapeutically effective amount of a substantially selective kappa-opioid-receptor agonist in a pharmaceutically acceptable preparation. In various embodiments, the kappa-opioid-receptor agonist may be devoid of activity on 5HT₂ receptors, in particular 5HT_(2A) receptors, such that it does not produce mania. In various embodiments, the kappa-opioid-receptor agonist also has D2 agonist activity and, in particular, partial D2 agonist activity. In certain embodiments, the kappa-opioid-receptor agonist may be salvinorin A.

In various aspects of this embodiment, the system may include, in addition to the kappa-opioid-receptor agonist, either or both of a cannabinoid compound and Ketamine in a pharmaceutically acceptable preparation. The pharmaceutically acceptable preparation for the cannabinoid compound and/or ketamine may include the same carrier system in which the kappa-opioid-receptor agonist is administered and the substances may be administered together or separately in any combination thereof. Alternatively, the carrier system for the cannabinoid compound and/or ketamine may be different from that of the kappa-opioid-receptor agonist and the substances may be administered separately. In some embodiments, naltrexone is included.

DETAILED DESCRIPTION OF THE INVENTION

The present invention involves the treatment of neuropsychiatric conditions and disorders by administration of a substantially selective kappa-opioid-receptor agonist in a pharmaceutically acceptable preparation. Administration may be intranasal, transdermal or by inhalation. The substantially selective kappa-opioid-receptor agonists include, in particular, salvinorin A as well as derivatives of salvinorin A (see for example U.S. Pat. No. 7,687,538, which is incorporated by reference).

As used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.

Salvia is the genus name for annual, biennial, or perennial herbs in the mint family. Salvia divinorum is a species containing psychoactive compounds, of which the diterpenoid compound, salvinorin A, is the principal component. Salvinorin A is a selective kappa-opioid-receptor agonist (Roth et al., 2004) and D2 receptor partial agonist (Seeman et al., 2009) with no substantial effect on 5-HTP_(2A) receptors (Roth et al., 2004).

Cannabis is the genus name for the annual, dioecious flowering herb in which psychoactive constituents, principally tetrahydrocannabinol (THC), occur in the floral calyces. Cannabis plants include Cannabis sativa, Cannabis indica, and Cannabis ruderalis as well as various crosses and hybrids. There are also known strains of Cannabis including “drug” strains which contain high levels of THC and low levels cannabidiol (CBD) and “non-drug” strains such as hemp which contain high levels of CBD and low levels of THC.

The term “cannabinoid compound” as used herein, is intended to refer to terpenophenolic compounds that act on cannabinoid CB₁ and/or CB₂ receptors in cells including phytocannabinoids, endocannabinoids and synthetic cannabinoids. Phytocannabinoids can be found in Cannabis plants, endocannabinoids are produced naturally in the body and synthetic cannabinoids are man-made.

Examples of phytocannabinoids include cannabigerol (CBG), cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC), cannabinol (CBN), cannabielsoin (CBE), iso-tetrahydrocannabinol (iso-THC), cannabicyclol (CBL) and cannabicitran (CBT).

The endocannabinoids bind to central (CB₁) and peripheral (CB₂) cannabinoid receptors. Examples of endocannabinoids include arachidonoylethanolamine (anandamide), 2-arachidonoylglycerol, 2-arachidonyl glyceryl ether, N-arachidonoyl dopamine and lysophosphatidylinositol.

Numerous synthetic cannabinoids have been made some of which have been used medicinally, for example, nabilone and rimonabant.

The term “cannabinoid compound” can also refer to any individual cannabinoid or combination of cannabinoid compounds such as the non-limiting example of THC+CBD+CBN or any other combination.

The term “about” when used before a numerical designation, e.g., pH, temperature, amount, concentration, and molecular weight, including range, indicates approximations which may vary by (+) or (−) 5%, 1% or 0.1%.

As used in the specification and claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a pharmaceutically acceptable carrier” may include a plurality of pharmaceutically acceptable carriers, including mixtures thereof.

The term “and/or” is intended to mean either or both of two components of the invention.

The term “subject,” “individual” or “patient” is used interchangeably herein, and refers to a human.

The term “agonist,” as used herein, refers to a moiety that interacts with and activates a receptor, and thereby initiates a physiological or pharmacological response characteristic of that receptor. The term “antagonist,” as used herein, refers to a moiety that competitively binds to a receptor at the same site as an agonist (for example, the endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor and can thereby inhibit the intracellular responses by an agonist or partial agonist. An antagonist does not diminish the baseline intracellular response in the absence of an agonist or partial agonist. The term “inverse agonist” refers to a moiety that binds to the endogenous form of the receptor or to the constitutively activated form of the receptor and which inhibits the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of an agonist or partial agonist.

The term “device,” as used herein, refers to an apparatus or system capable of delivering a drug to patient in need thereof.

The term “in need of treatment” and the term “in need thereof” when referring to treatment are used interchangeably and refer to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, that a patient will benefit from treatment.

The term “nostril,” as used herein, is synonymous with “naris.”

The term “nasal delivery”, “intranasal delivery”, “nasal administration” or “intranasal administration” refers to a route of administration wherein the pharmaceutical dosage form is taken to, or through, the nose (e.g., nasal cavity). Similarly, a “nasal delivery device” or an “intranasal delivery device” is intended to mean an apparatus that administers a drug into the nasal cavity. Non-limiting examples of intranasal administration include introduction of a solution or suspension in the form of a nasal spray or drops (direct instillation) or intranasal application of gel, emulsion or ointment.

The term “inhalation delivery” or “inhalation administration” refers to a route of administration wherein the pharmaceutical dosage form is taken into the airways and lungs by inhaling a gaseous, vaporized, or aerosolized drug preparation. Similarly, an “inhalation delivery device” is intended to mean an apparatus that administers a drug into the airways and lungs. The drug preparation may aerosolized using, e.g. a nebulizer.

The term “transdermal delivery” refers to a route of administration in which the pharmaceutical dosage form is taken up through the skin. Similarly, a “transdermal delivery device” is intended to mean any apparatus or system that administers a drug to be taken up through the skin.

The term “pharmaceutically acceptable,” as used herein, refers to a component of a pharmaceutical composition that is compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered and includes, but is not limited to such liquids and powders that are hydrophilic substances, hydrophobic substances and substances that possess both hydrophilic and hydrophobic properties such as emulsifiers.

By the term “substantially selective kappa-opioid-receptor agonist” it is meant that the agent has an affinity for kappa-opioid receptors and/or kappa-opioid biological activity, for example EC₅₀ (concentration of compound that gives half-maximal response) of at least 10-fold, at least 100-fold, at least 1000-fold or greater than that for mu- and delta-opioid receptors (see for example, Cunningham, 2011).

The term “substantially no effect on 5HT₂ receptors” and, in particular “substantially no effect on 5HT_(2A) receptors” is intended to mean a compound has receptor affinity and/or elicits receptor mediated biological activity that is less than 0.1, less than 0.01, less than 0.001 or lesser than that for the kappa-opioid receptor (see for example Roth, 2004). Similarly, the term “produces substantially no manic effect” it is meant that the compound does not produce a meaningfully significant manic effect in a population of subjects.

The term “therapeutically effective amount,” as used herein, refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, or individual that is being sought by a researcher, healthcare provider or individual.

Intranasal delivery devices are known in the art. Thus, any device suitable for delivery of drug to nasal mucosa may be used. Non-limiting examples of devices useful for the administration of liquid compositions include vapor devices (e.g., vapor inhalers), drop devices (e.g., catheters, single-dose droppers, multi-dose droppers, and unit-dose pipettes), mechanical spray pump devices (e.g., squeeze bottles, multi-dose metered-dose spray pumps, and single/duo-dose spray pumps), bi-directional spray pumps (e.g., breath-actuated nasal delivery devices), gas-driven spray systems/atomizers (e.g., single- or multi-dose HFA or nitrogen propellant-driven metered-dose inhalers, including traditional and circumferential velocity inhalers), and electrically powered nebulizers/atomizers (e.g., pulsation membrane nebulizers, vibrating mechanical nebulizers, and hand-held mechanical nebulizers). Non-limiting examples of devices useful for the administration of powder compositions (e.g., lyophilized or otherwise dried pooled compositions) include mechanical powder sprayers (e.g., hand-actuated capsule-based powder spray devices and hand-actuated powder spray devices, hand actuated gel delivery devices), breath-actuated inhalers (e.g., single- or multi-dose nasal inhalers and capsule-based single- or multi-dose nasal inhalers), and insufflators (e.g., breath-actuated nasal delivery devices).

Inhalation delivery devices are known in the art. Thus, any device suitable for delivery of drug to the lungs may be used. Non-limiting examples of suitable inhalation devices for inhalation include various types of modern inhalers based on different aerosolization technologies. For example, a metered-dose inhaler, a dry powder inhaler, a soft mist inhaler, or a nebulizer may be used. Metered-dose inhalers are typically pressurized, i.e. the active ingredient and optional inactive constituents are dispersed or dissolved in a liquid, pressurized propellant. A metered-dose inhaler typically comprises a canister which may be made of plastic, glass, aluminum, stainless steel, or any other suitable material; a metering valve allowing a metered quantity of the formulation to be dispensed with each actuation; and an actuator which is often combined with a mouthpiece to allow the subject to operate the device and direct the aerosol into the patient's lungs via the mouth.

Transdermal delivery devices are known in the art. Thus, any device suitable for delivery of drug across the skin of a patient may be used. Devices known in the art include reservoir type devices involving membranes that control the rate of drug release to the skin and devices where the drug is dispersed or dissolved in a matrix such as a pressure sensitive adhesive. Transdermal delivery devices may be made in the form of an article such as a tape, a patch, a sheet, a dressing or any other form known to those skilled in the art. Generally, the device may in the form of a patch of a size suitable to deliver a preselected amount of drug through the skin. Generally, the device will have a surface area of about 5 cm² to about 100 cm² and, in particular, about 10 cm² to about 40 cm².

Transdermal drug delivery devices typically involve a carrier (such as a liquid, gel, or solid matrix, or a pressure sensitive adhesive) into which a compound of the invention is incorporated.

For inhalation, or intranasal administration the preparation may contain a compound of the invention in a liquid carrier for aerosol application. In various embodiments, the composition may be in the form of an aqueous or non-aqueous solution, suspension, liposomal dispersion, emulsion, microemulsion or a combination thereof. The carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, mucoadhesives and/or preservatives such as parabens.

Methods well known in the art for making formulations may be found, for example, in Remington, 2000. Further, methods for formulating compounds for intranasal and transdermal administration, including for extending the presence in in the nasal cavity, creating various emulsions, combining with cyclodextrins and other agents to enhance solubility, creating prodrugs, analogs, and increasing bioavailability, etc. are well known. See, e.g., Bitter et al., 2011; Pastore et al., 2014.

The compounds of the present invention may be used for the treatment of neuropsychiatric disorders including affective disorders such as depression, bipolar disorder or anxiety disorder. Thus, the compounds may be used to treat abnormalities of mood or emotion including depression, bipolar disorder, dysthymia, post-traumatic stress disorder, schizoaffective disorder, schizophrenia and other psychotic disorders, anxiety disorders, panic disorder, traumatic stress disorders, phobic disorders, and personality disorders with abnormal mood, such as borderline personality disorder, schizoid and schizotypal disorders and suicide ideation.

The compounds of the present invention may also be used for treating addiction. Such addictions may be addiction to drugs, non-limiting examples of which may include nicotine, alcohol, cocaine, opioids, amphetamine, methamphetamine, heroin, morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well as other addictive substances. Additions may also include addictive behaviors, non-limiting examples of which may include eating, gambling, sex, pornography, videogames, work, exercise, spiritual obsession, self-harm, travel and shopping addiction.

Salvinorin A may be administered as Salvia divinorin or in a purified form of salvinorin A. When Salvia divinorin is administered, the dose is calculated in terms of the amount of salvinorin A administered from the preparation. The dose of salvinorin A when administered by inhalation may be in a range of from as low as about 50 μg, about 75 μg, about 100 μg, about 250 μg or about 400 μg up to about 500 μg, about 1000 μg, about 2000 μg, about 5000 μg or about 10,000 μg. The dose of salvinorin A when administered intranasally may be in a range of from as low as about 5 μg, about 7.5 μg, about 10 μg, about 25 μg or about 50 μg or about 100 μg up to about 200 μg, about 500 μg, about 1000 μg, about 2000 μg, about 5000 μg or about 10,000 μg. The dose of salvinorin A when administered transdermally may be in a range of from as low as about 5 μg, about 7.5 μg, about 10 μg, about 25 μg or about 50 μg or about 100 μg up to about 200 μg, about 500 μg, about 1000 μg, about 2000 μg, about 5000 μg or about 10,000 μg.

Ketamine may be administered intranasally as the hydrochloride at a dose in a range of from as low as about 5 μg, about 10 μg, about 20 μg, about 30 μg up to about 75 μg, about 125 μg, about 200 μg, or about 300 μg. In some embodiments, naltrexone is also administered to potentiate the effects of the ketamine administration.

The cannabinoid compound may be administered by combustion and inhalation of the floral calyces of a Cannabis plant or in a purified form of the cannabinoid compound. When Cannabis plant is administered, the dose is calculated in terms of the amount of the cannabinoid compound administered from the preparation. The dose of the cannabinoid compound when administered by inhalation may be in a range of from as low as about 200 μg, about 500 μg, about 1000 μg, about 2000 μg or about 5 μg up to about 10,000 μg, about 15,000 μg, about 20,000 μg, about 25,000 μg, about 50,000 μg, about 75,000 μg, about 100,000 μg, about 150,000 μg, or about 250,000 μg, or about 500,000 μg or about 750,000 μg, or about 1,000,000 μg, or about 1,500,000 μg or about 2,000,000 μg, or about 2,500,000 μg, or about 3,000,000 μg, or about 3,500,000 μg, or about 4,000,000 μg, or about 4,500,000 μg, or about 5,000,000 μg.

Administration may be once a day (q.d.), twice a day (b.i.d.), three times a day (t.i.d.), four times a day (q.i.d.) or at more or less frequent intervals such as once every other day (q.a.d.), once every third day, twice a week (bis in 7 d.), once a week (QWK), once every other week, etc. Alternatively, administration may be as needed (p.r.n.).

Preferred embodiments are described in the following examples. Other embodiments within the scope of the claims herein will be apparent to one skilled in the art from consideration of the specification or practice of the invention as disclosed herein. It is intended that the specification, together with the examples, be considered exemplary only, with the scope and spirit of the invention being indicated by the claims, which follow the examples.

Example 1. Salvinorin a Administration is Anxiolytic, Antidepressant and Motivationally Stimulating with No Manic Side Effects

The effects of salvinorin A were evaluated in one subject with bipolar disorder following Salvia divinorum administration by combustion and inhalation at a dose of approximately 8 mg of enhanced leaf of ‘regular strength’ from a known online source (sagewisdom.com). After a brief, 2-5 minute period of mild hallucinations accompanied by euphoria, the subject experienced anxiolytic, antidepressant and motivationally stimulating effects for a period of 24 hours or greater with no manic side effects. It is noteworthy that this subject had experienced mania even on very small, sub-therapeutic doses of traditional antidepressants including celexa and sertraline—serotonin agonists and partial agonists. A slight tremor appeared shortly after administration, however, co-administration of cannabis by combustion and inhalation along with the Salvia divinorum eliminated the tremor. This method was repeated approximately 20 times with consistent results.

Co-administration of cannabis by combustion and inhalation and/or ketamine (ketamine hydrochloride, at varying doses, generally about 30 to about 75 mg) by intranasal administration along with Salvia divinorum by combustion and inhalation appeared to potentiate the anxiolytic and antidepressant effects of Salvia divinorum alone.

The subject also takes clonazepam, orally and/or sublingually, and has reported that clonazepam (at varying doses, generally about 1.5 mg, b.i.d. and occasionally, about 0.5 mg up to about 2.5 mg p.r.n.), along with co-administration of cannabis by combustion and inhalation and/or ketamine by intranasal administration with Salvia divinorum by combustion and inhalation appeared to potentiate the anxiolytic and antidepressant effects of the Salvia divinorum alone and helped to further alleviate any anxiety, tremor or any other side effect before, during or after administration of the Salvia divinorum.

Example 2. Effects of Intranasal or Transdermal Administration of Salvinorin a on Behavioral Activity

Preparation of the intranasal and transdermal salvinorin A is by known methods. See, e.g., Bitter et al., 2011; Pastore et al., 2015.

Following intranasal or transdermal delivery of salvinorin A at 3 separate dosages, with a negative control administered vehicle only, rats are monitored for a total of 40 minutes by an experimenter who is blinded to condition. Signs of altered behavior, including staring, immobility, increased or decreased response to stimuli (e.g. tactile, auditory), and changes in locomotor patterns are recorded.

For each method of administration, a total of 48 Sprague-Dawley male & female CD rats ˜45 days old are utilized (Table 1).

TABLE 1 Summary of Treatment Groups Number Group Treatment Purpose ♂ ♀ T-1 Concentration 1 Test Article (Dose 1) 6 6 T-2 Concentration 2 Test Article (Dose 2) 6 6 T-3 Concentration 3 Test Article (Dose 3) 6 6 C-1 Vehicle only Negative Control 6 6

Following a 5-7 day acclimation phase, rats are randomly divided into 4 groups (Cl, T1, T2, T3; Table 1) and receive intranasal or transdermal administration of the appropriate dosage of Compound X.

Visual (real-time) monitoring is performed for 10 minutes pre-administration and 30 minutes post-administration of the compound.

Animals are observed in real time to assess behavioral anomalies, with 4 animals monitored simultaneously (1 from each condition). Periods of staring, increased or decreased response to stimuli (e.g. tactile, auditory), and any other unusual behaviors are noted. Animals are also video recorded, with locomotor activity, rearing, grooming, and periods of immobility assessed using the AnyMaze™ behavioral scoring system (Stoelting Co., Wood Dale IL 60191 US). All behavioral evaluations are performed by an experimenter blinded to condition. The following 2 phases are used to allow for within and between animal comparisons:

Parametric data is evaluated using 2-way ANOVA (SEX by TREATMENT). Statistically significant main effects are further investigated using Tukey's post hoc analysis. Non-parametric analyses are assessed using a Kruskal-Wallis test with Dunn-Bonferroni pairwise comparisons for post hoc analysis. Significance level for all tests is p≤0.05.

Example 3. Effects of Intranasal or Transdermal Administration of Salvinorin A on Anxiety

Salvinorin A is administered intranasally or transdermally to rats at one of 3 different dose levels (1, 2 or 3). In addition to a normal control, there is both a positive and a negative control group. For the positive control, rats receive a 5 mg/kg injection (i.p.) of tracazolate, a non-benzodiazepine anxiolytic compound (Thompson et al., 2002). As a negative control, FG7142 (5 mg/kg i.p.) is administered to produce anxiogenic behavior (Pellow and File, 1986). The normal control group receives an i.p. injection of an equivalent volume (2 ml/kg) of sterile saline. All control groups also receive an equivalent volume of vehicle delivered in an identical manner to that used for the test article (i.e. intranasal or transdermal administration).

A total of 60 Sprague-Dawley male CD rats ˜45 days old are utilized for each administration method (Table 2).

TABLE 2 Summary of Treatment Groups Group Treatment Purpose Number T-1 Concentration 1 Test Article (Dose 1) 10 T-2 Concentration 2 Test Article (Dose 2) 10 T-3 Concentration 3 Test Article (Dose 3) 10 Veh Vehicle Normal Control 10 Pos Tracazolate Anxiolytic 10 Neg FG7142 Anxiogenic 10

Following a minimum 7 day acclimation phase, rats are randomly divided into 6 groups (T1, T2, T3, Veh, Pos, Neg; Table 2).

Forty-five minutes prior to behavioral testing, an i.p. injection is administered to all animals in a volume of 2 ml/kg as follows: rats in the anxiolytic control group, receive tracazolate (5 mg/kg), a pyrazolopyridine that reduces anxiety-like behaviors in rodents (Pellow and File, 1986), an effect believed to result from allosteric modulation of extrasynaptic GABAA receptor function (Thompson et al., 2002; Belelli et al., 2009). As an anxiogenic control, a second group of rats receive FG7142 (N-methyl-pf-carboline-3-carboxamide), a beta-carboline that acts as a partial inverse agonist at the benzodiazepine allosteric site (Evans and Lowry, 2007) and produces demonstrated increases in anxiety-like behaviors in various tasks (Thompson et al., 2002; Arrant et al., 2013). Rats in experimental groups (i.e. those who have received a test compound), as well as rats in the normal control group receive an injection of sterile saline.

Thirty minutes prior to behavioral testing, rats in test article groups receive intranasal or transdermal administration of salvinorin A at one of the 3 dosage levels. Animals in the normal control group receive administration of vehicle only in a volume equivalent to that utilized for the experimental animals. Following treatment as per its assigned group, each rat is tested in either the Open Field (OF) test or the Elevated Plus Maze (EPM) to assess anxiety-like behaviors. One week later, the same rats receive the same group treatment (experimental or control) and undergo testing in the paradigm not yet experienced (i.e. OF or EPM). All tests are video recorded for scoring and documentation purposes.

Ultrasonic vocalizations (USVs) is also recorded and analyzed to provide an additional level of anxiety-related measures.

The following behavioral tests are performed:

Elevated Plus test (Bailey and Crawley, 2009)—The arena for this test consists of four arms, two with sidewalls, and two open (a “plus” configuration), thus providing a measure of anxiety associated with open space, unprotected regions. The maze is elevated ˜2 feet above the floor. Rats are started in the center (neutral) zone of the test, and behavioral measures include latency to enter and percent of time spent in the closed arms as recorded during a 10 minute trial.

Open Field test (Gould et al., 2009)—The open field test allows assessment of activity levels, locomotion, and anxiety-related behaviors. Rats are started in the center of the arena (˜4.5 foot diameter), and measures during a 10 minute test period may include: latency to reach the outer wall region, time spent in thigmotaxic behavior, number of entries into and time spent in the center region, distance travelled, average speed in each region, number and time spent rearing, number and time spent grooming, and comparison of activities during the first and last minute, and first and last half of the task.

Ultrasonic Vocalizations—Ultrasonic vocalization emissions are recorded during testing, with number, duration, and frequency range of calls assessed to provide an additional measure of affective state during testing. See also Bourin, 2015; and Campos et al., 2013.

Example 4. Antidepressant Effects of Intranasal or Transdermal Administration of Salvinorin A

For confirming its antidepressant effects, salvinorin A is administered intranasally or transdermally to rats at one of 3 different dose levels (1, 2 or 3), with a control group that receives an equivalent volume of vehicle delivered in an identical fashion to the test article.

A total of 40 Sprague-Dawley male CD rats ˜45 days old are utilized for each administration method (Table 3).

TABLE 3 Summary of Treatment Groups Group Treatment Purpose Number T-1 Concentration 1 Test Article (Dose 1) 10 T-2 Concentration 2 Test Article (Dose 2) 10 T-3 Concentration 3 Test Article (Dose 3) 10 Veh Vehicle Normal Control 10

Following the acclimation phase, rats are randomly divided into 4 groups (T1, T2, T3, Veh; Table 3).

On the day of the test phase, ultrasonic vocalization (USV) emissions are recorded from each rat at 3 time points—prior to compound administration, immediately following compound administration, and immediately after the test phase. Thirty minutes prior to the test phase, rats in experimental groups receive intranasal or transdermal administration of the appropriate dosage of salvinorin A (T-1, T-2, or T-3). Rats in control groups receive an equivalent volume of vehicle delivered in an identical manner.

Following treatment as per its assigned group, each rat is tested in the Forced Swim Test (FST) to assess depressive behaviors. All tests are video recorded for scoring and documentation purposes.

The forced swim test is based on a rodent's aversion to water, and subsequent desire to try and escape when submerged. To induce the model, rats are placed in an inescapable water-filled container (˜8″ diameter×20″ deep) for 15 minutes (pre-test phase). Duration of struggling/climbing, immobility, and swimming activities are measured during each 5 minute block to provide a baseline evaluation. Twenty-four hours later, rats are once again placed in an inescapable water-filled container, and measures are recorded for 5 minutes (test phase).

To provide an additional level of affective state, USV emissions are recorded for 5 minutes prior to, and following, the pre-test phase. In addition, USVs will be recorded on the testing day for 5 minutes prior to the test phase, 5 minutes immediately following compound administration, and 5 minutes following the test phase.

Parametric data is evaluated using ANOVA, with repeated measures utilized where appropriate. Statistically significant main effects are further investigated using Tukey's post hoc analysis. Non-parametric analyses will be assessed using a Kruskal-Wallis test with Dunn-Bonferroni pairwise comparisons for post hoc analysis. The Friedman test will be used to evaluate non-parametric repeated measures data. Significance level for all tests will be p≤0.05.

See also Bogdanova et al., 2013; Krishnan and Nestler, 2011; Abelaira et al., 2013; Gould and Einat, 2007; and Abulseoud et al., 2014.

Example 5. Effects of Intranasal or Transdermal Administration of Salvinorin A on Chronic Depression

Chronic exposure to mild, unpredictable stress is used as a rodent model of long-term depression. This paradigm results in decreased consumption of sweetened water, a treat that is generally rewarding to rats.

For confirming its effects on chronic depression, salvinorin A is administered intranasally or transdermally to rats at one of 3 different dose levels (1, 2 or 3), with a control group that receives an equivalent volume of vehicle delivered in an identical fashion to the test article.

A total of 60 male Wistar CD rats ˜45 days old are utilized for each administration method (Table 4).

TABLE 4 Summary of Treatment Groups Group Treatment Stress Purpose Number A Compound X1 Yes Test Article Dose 1 12 B Compound X2 Yes Test Article Dose 2 12 C Compound X3 Yes Test Article Dose 3 12 D Vehicle Yes Negative Control 12 E Vehicle No Normal Control 12

Starting 24 hours after arrival in the facility, rats will be acclimated to a sugar water solution (1% sucrose), to avoid neophobic behaviors during the testing period. Baseline measures of sucrose preference will be obtained prior to model induction.

Upon study initiation, rats are randomly divided into 5 groups (X1, X2, X3, Negative Control, Normal Control; Table 4).

Chronic mild stress protocols are performed for a 6 week period as outlined below, with a 24 hour sucrose preference test administered weekly.

For the final 3 weeks of the chronic mild stress protocol, each rat receives daily salvinorin A administration as per its assigned group. Control (non-stressed) rats receive an equivalent volume of vehicle, delivered in an identical fashion as the test article. As during the induction phase, a 24 hour sucrose preference test is administered weekly.

To produce a model of chronic depression, a series of mild, unpredictable stressors will be utilized, with protocols adapted from previous literature (Harden et al., 2012; Lopez-Lopez et al., 2016; Papp et al., 1996). A decrease in consumption of a rewarding treat (sugar water) over a 24 hour presentation period (tested once per week; see Behavioral Testing section below) is considered indicative of depressed behavior (anhedonia).

Stressors to be utilized include a 16 hour food deprivation period, 15 hour water deprivation followed by 1 hour empty water bottle presentation, 36 hours continuous light, 9 hours wet cage bedding, 15 minute immersion in cold water, 5 hour foreign object presentation (some objects will restrict movement in cage), 5 hours inclined (45° cage), and 3 hours noise (40 dB) to be presented with or without other stressors.

Prior to model induction, a baseline level for sucrose preference is established over a 24 hour period as outlined below.

Sucrose Preference Testing—Once per week, for a 24 hour period, regular water bottles will be replaced with two pre-weighed bottles, one containing regular water, and one with a 1% sucrose solution (sugar water). After 24 hours, bottles will be weighed again, and consumption of each will be recorded. No stressors will be administered during or for 12 hours prior to this time period.

Parametric data will be analyzed using ANOVA, with repeated measures where appropriate. Statistically significant main effects will be further investigated using Tukey's post hoc analysis. Significance level for all tests will be p≤0.05.

See also Lynch et al., 2010 and Planeta, 2013.

Example 6. Effects of Intranasal or Transdermal Administration of Salvinorin A on Addictive Behaviors

Reinforcing effects of drugs of abuse are believed to play a key role in substance abuse and addiction; paradigms that measure drug reinforced behaviors allow for evaluation of compounds that may interfere with these processes. The conditioned place preference paradigm provides assessment of a drug's rewarding effects, and when used with a known addictive substance, the paradigm allows for screening of compounds with potentially therapeutic benefits.

For confirming its effects on addictive behaviors, salvinorin A is administered intranasally or transdermally to rats at one of 3 different dose levels (1, 2 or 3), with a control group that receives an equivalent volume of vehicle delivered in an identical fashion to the test article.

Control groups are saline only exposure (negative control) or cocaine only exposure (positive control) plus administration of an equivalent volume of vehicle delivered in an identical fashion to the test article (i.e. intranasal administration).

A total of 50 Sprague-Dawley male SD rats ˜45 days old upon arrival in the facility will be utilized for each administration method (Table 5).

TABLE 5 Summary of Treatment Groups Group Treatment Purpose Number A Compound X1 Test Article Dose 1 10 B Compound X2 Test Article Dose 2 10 C Compound X3 Test Article Dose 3 10 D Saline/vehicle Negative Control 10 E Cocaine/vehicle Positive Control 10

Upon study initiation, rats are randomly divided into 5 groups (X1, X2, X3, Pos, Neg; Table 5). All phases of the study are performed under reverse light cycle.

One day prior to the habituation phase of the study, rats receive a single intraperitoneal (i.p.) injection of saline prior to being returned to the home cage.

During habituation, rats are exposed to the testing apparatus for 15 minutes per day for 3 days.

During the conditioning phase, each animal is administered the appropriate compound (cocaine or saline alternated over days) and immediately be placed in the associated chamber (drug or vehicle as appropriate) of the apparatus for 30 minutes per day for 8 consecutive days. Saline control animals receive saline only each day, with chamber presentation alternated over days.

On the testing day, 24 hours after the last conditioning trial, each rat receives intranasal or transdermal compound administration as per its assigned group, and is tested at the post-administration time point as specified by the sponsor to determine the effects of the various dosage levels of the compound on cocaine-induced CPP. All tests are video recorded for scoring and documentation purposes by experimenters blinded to rat condition.

An i.p. injection of either cocaine (20 mg/kg) or saline in a maximum volume of 10 ml/kg will be administered to rats during conditioning trials as specified in the behavioral testing section below.

The following behavioral tests are performed:

Cocaine-induced Conditioned Place Preference test (CPP)(Buccafusco, 2009; Galaj et al. 2014)—This test provides an assessment of the degree of reward associated with cocaine administration. The testing apparatus consists of two compartment chambers plus a center “tunnel” area (unforced choice) separated by doors, with the two larger outer chambers varying in both color (e.g. black vs white) and floor texture (e.g. horizontal grid vs cross-grid). The center connecting chamber has no special characteristics, is not paired with any compound and is not accessible during habituation. Measures that are evaluated include time spent in each chamber, first chamber chosen, chamber entries, speed, and distance travelled.

There are three stages:

-   -   1) Habituation—rats are placed in the test apparatus and allowed         free access for 15 minutes per day for a total of 3 days to         eliminate novelty as a confounding variable. Time spent in each         compartment is recorded to determine compartment preference         prior to conditioning.

In order to habituate rats to injections, an i.p. injection of saline is administered one day prior to the first apparatus exposure. Following this injection, rats are placed back in their home cage.

-   -   2) Conditioning—rats are conditioned over 8 consecutive days,         with cocaine administration repeated once every other day for a         total of 4 cocaine conditioning days. On cocaine conditioning         days, rats are given an injection of cocaine (20 mg/kg i.p.),         and are immediately confined for 30 minutes in the compartment         for which they showed the least preference during the         habituation stage (biased procedure). On alternate days, rats         are given an injection of saline, and are confined to the         opposite chamber to that utilized during cocaine conditioning.         The order of cocaine conditioning is counterbalanced across         rats. One group of rats (negative control) will receive a daily         injection of vehicle only and alternately be exposed to each         compartment.     -   3) Testing—24 hours following the last conditioning session, all         rats receive intranasal administration of the appropriate test         article dose or an equivalent volume of vehicle. Cocaine-induced         CPP is assessed by placing the rat in the center compartment and         allowing free access to the entire apparatus for 15 minutes.         Time spent in each compartment is measured.

Parametric data will be analyzed using ANOVA. Statistically significant main effects are further investigated using Tukey's post hoc analysis. Significance level for all tests will be p≤0.05.

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In view of the above, it will be seen that several objectives of the invention are achieved and other advantages attained.

As various changes could be made in the above methods and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

All references cited in this specification are hereby incorporated by reference. The discussion of the references herein is intended merely to summarize the assertions made by the authors and no admission is made that any reference constitutes prior art. Applicants reserve the right to challenge the accuracy and pertinence of the cited references. 

What is claimed is:
 1. A method of treating tremor caused by administration of a substantially selective kappa-opioid-receptor agonist in a patient, the method comprising: administering ketamine and/or a cannabinoid in a pharmaceutically acceptable preparation sufficient to treat the tremor.
 2. The method of claim 1, wherein the substantially selective kappa-opioid-receptor agonist is salvinorin A.
 3. The method of claim 2, wherein the salvinorin A is administered intranasally.
 4. The method of claim 2, wherein the salvinorin A is administered transdermally.
 5. The method of claim 1, wherein the salvinorin A is administered by combustion and inhalation.
 6. The method of claim 1, wherein the patient has an affective disorder.
 7. The method of claim 6, wherein the patient is treated with the substantially selective kappa-opioid-receptor agonist to treat the affective disorder.
 8. The method of claim 7, wherein the substantially selective kappa-opioid-receptor agonist is salvinorin A.
 9. The method of claim 6, wherein the affective disorder is depression, bipolar disorder, anxiety disorder, or depression.
 10. The method of claim 1, wherein the patient has an addiction.
 11. The method of claim 10, wherein the patient is treated with the substantially selective kappa-opioid-receptor agonist to treat the addiction.
 12. The method of claim 11, wherein the substantially selective kappa-opioid-receptor agonist is salvinorin A.
 13. The method of claim 10, wherein the addition is to an addictive behavior selected from the group consisting of eating, gambling, sex, pornography, video games, work, exercise, spiritual obsession, self-harm, travel and shopping addiction.
 14. The method of claim 1, wherein ketamine is administered without a cannabinoid.
 15. The method of claim 1, wherein a cannabinoid is administered without ketamine.
 16. The method of claim 1, wherein both ketamine and a cannabinoid is administered.
 17. The method of claim 1, wherein the cannabinoid is administered by combustion and inhalation.
 18. The method of claim 1, wherein the cannabinoid is administered by inhalation of a vaporized preparation.
 19. The method of claim 1, wherein the ketamine is administered intranasally. 